Esters of 19-nortestosterone



United State Pa q o 2,998,423 ESTERS OF 19-NORTESTOSTERONE Erik 'DuyvenDe Wit, Oss, and Gerhard Anthony Overbeek, Nijmegen, Netherlands,assignors to Organon ice The compounds according to the invention are17-esters of 1'9-nortestosterone and saturated and unsaturated aliphatic carboxylic acids having 9-4 8 carbon atoms.

These compounds can be prepared by converting hm West range,NJ acoulomb-on of New Jersey l9-nortestosterone into said esters in a mannerknown No brawing. Filed Fb. 2, 1959, Ser. No. 790,357 P so for ester a in, for example y reacting Claims priority, application Netherlands Feb.25, 1958 19-nortestosterone dissolved in a suitable solvent with the 4Claims. (Cl. 260-4974) acid chloride of the desired acid or with theanhydride of said acid. V The present invention pertains to new estersof 19-n0r: 10 Th t ti f th fi t f compounds n th rel tion testosterone.between anabolic and androgenic activity is mostly car It is known thattestosterone and esters thereof have an ied out b means f tests oncastrated rats, i hi h. anabolic effect in addition 10 a andmganiceffect some time after the administration of the compound to- Owing totheir anabolic activity these compounds have be tested the weights ofthe musculus-levator ani andi been applied for example in the treatmentof cancer of of h Seminal vesicles i determined, the breast, in which,however, the virilizing efiect is most At the same time the weights ofthese organs areundesirable. One hasv therefore long been seekingtor dter ined of rats of the same age to which the com"- compounds that dohave an anabolic but y a sllght pound in question has not beenadministered but which virilizing effect. have been treated further inquite the same manner. Esters of l9-nortestosterone are descrlbed, theana- The difference in weight of the musculi levator ani li ndandrogenic i y of which are y f (AMLA) then is a measure for theanabolic and thatof ably d- These arethe esters of l9-nortestostero nethe seminal vesicles (ASV) for the androgenic activity; and alipha'ilccyclo-allphatlc-allphatlc ay a aclqs So the relation AMLA/ ASP is ameasure for the rela- With 9 t0 Flght carbon atoms aromatlo'allp hatlotion between anabolic and androgenic activity. g j t of whlch theahphatlc Part contams 2 With substances which are destined for clinicalapor car onaoms.

pl1cat1on it is desirablerthat th1s relation is as great as i i i estersf of '19 g z ig i possible. This relation should not only be favourable.at figgfgl b zzg ggi ig i g p g 55 g g a g a certain time afteradministration, but should maintain anabolic and androgenic activity isthe most favouri faqourable value as long substance m able. Consequentlythis compound is applied in a very ex erts some S0 it may not be W tlarge number of cases, of which may be mentioned by after in ection thesubstance has a good anabohc effect way of example cancer of the breast,osteoporosis, and a Shght "mhzmg efiect, Whllo thls would be th Vdecubitus, retarded growth, asthenia, osteogenesis imother Way aboutafter f 875511111916 a Weekperfecta and for which further reference maybe made o above f 111 Whloh AMLA/ASV to the very extensive medicalliterature on this compound. mllled, rs v ry Suitable for testinganabolic compounds;

Although in most of the cases excellent results are obbficausa has ppthat there is a very good'correlatained with this known compound, theneed remains for 11011 between the effect 0f the substances in test andanabolically acting compounds having a more prolonged 40 on clinicalapplication. I effect than the l9-nortestosterone fl-phenylpropionate IThe present compounds have been tested according to (hereinafterindicated by nor-TPP). In addition one the above method and comparedwith the compound is searching for compounds in which the relationbetween S0 far known to be the compound having the most favour-1 theanabolic and the androgenic effect is even more able relation betweenanabolic and androgenic efrect, viz.- favourable than in the nor-TPP'.the nor-TPP. I 7

It is an object of this invention to provide new esters 1 The followingresults were obtained (each figure is of l9-nortestosterone the relationof the anabolic and the the result of an experiment performed with 8rats weigh: androgenic effect of which is more favourable than in the mgabout grams when the experiment started); nor-TPP and which have aduration of action which is The treatment consists of a singleadministration of substantially longer than that of the nor-TPP.. 50 1mg. ofthe compound in question.

Effect after2 weeks Effect after 4 Weeks Effect after 6 weeks TreatmentAMLA ABV AMLA/ AMLA ASV AMLA/ AMLA ASV AMLAI. Asv ASV ASV q nor-TPP 21.49.7 '22 5.3 5.4 7.0 7.1 19-n0rtest.unde- 4 cylenate 25. 4 5. 0 5. 3 as.e 5. 0 7. 7 a2. 1 5. 5 5. o IQ-nortest. octene carboxylate 21.2 5.9 4.535.2 5.4 5.7 24.3 4.8 5.1 19-nortest. dodecene earboxylate 22. 8 6. 0 3.8 30. 3 5.1 5. 9 28. 6 3. 2 9.0 IQ-nortest. tetradecene carboxylate 22.54.5 4.9 22.4 4.2 5.3 20.1 3.7 5.4 19-nortest oleate 15. 8 3. 5 4. s 24.2 4. 0 6. 0 25. 7 4. 1 s. a 19-nortest. decan ate 25.0 2. 7 9. 2 e2. 75. 5 11.4 50 5. s 7. a 19-nortest. laurate.-- 23. 2 2. 7 8. 6 5. s 12 5s5. 9 s. 4 19-nortest. myria- 19. 4 2. 2 8. 8 42 4. 2 1o 43. 7 4.1 10. 719-nortest, palmt- It follows from this table that after 4 weeks theeffect of the nor-TPP has ceased practically entirely.

As with this compound AMLA is only very slight after the said period oftime, the statement of the value of AMLA/ASV has no purpose here(theoretically both ASV and AMLA would have to be nil if there is noefiect at all). It also appears from the table that the presentcompounds do not only have a larger proteinsaving effect but also aslighter androgenic effect, while even after 6 weeks a pronounced eifectis present.

That is the present compounds the relation between the anabolic and theandrogenic effect would be so favourable could by no means beanticipated, because it is known that on esterification of testosteronewith some of the acids in question the androgenic effect increases verystrongly. It was not to be expected that with nor-testosterone the veryanabolic effect and not the androgenic effect should be amplified tosuch a large extent.

The present compounds do not only have favourable efiects in the animalexperiment, but also on clinical application. It has appeared forexample in nitrogen balance experiments in men that in a certain casethe protein-saving effect of the nor-TPP which is applied on a verylarge scale amounted to about g. daily during the first 15 days afterinjection, whereas this with for example the nortestosteroneundecylenate and -decanoate amounted to about 25 g. daily afteradministration of an equal dose. This larger effect, added to the muchmore prolonged effect renders the present compounds very valuable forclinical application.

The initial effect of the 19-nortestosterone oleate and -palmitate issomewhat smaller than that of the other compounds; against this is themore prolonged efiect, as a result of which this compound becomes ofgreat importance for veterinary application, because for example by asingle injection in young pigs the protein formation can be promoted toa very great extent at the expense of the deposit of fat, as a result ofwhich an improved meat is obtained in a shorter time. Any unpleasanttaste of the meat, as is the case after injection of androgenicsubstances, need not be feared, because the androgenic effect of thesecompounds is negligible.

In addition to the acids with one double bond also acids with more thanone double bond may be considered for the present process, as well asacids with a triple bond.

In the process according to the invention start is preferably made fromthe acid chloride of the acid in question.

The following examples illustrate the process.

Example I (a) 1 g. of 19-nortestosterone is dissolved in 3 ml. of drypyridine, after which the resulting solution is cooled to 20 C. Asolution of 1. g. of undecylenic acid chloride in 3 ml. of dry benzeneis added to the cooled solution. The mixture is maintained at 15 C. for16 hours and then poured into ice water. The aqueous liquid is extractedwith benzene, the benzene solution is washed with respt. 1 N sodiumhydroxide solution, 2 N hydrochloric acid and with water till neutralreaction.

Then the solution is dried on sodium sulphate, filtered, and evaporatedto dryness. The residue, 1.63 g. is dissolved in hexane, this solutionis filtered over 30 g. of neutral aluminium oxide, and evaporated todryness. On paper chromatographic investigation it turned out that theobtained 19-nortestosterone l7-undecylenate which at room temperature isan oil consists of a single compound. [oz] =+39.6 (in chloroform). E15,600 (in ethanol).

(b) In the same manner as mentioned sub (a) the octene carboxylic esterof 19-nortestosterone is prepared in a yield of 88%. E ,,=15,900 (inethanol).

(0) In the same manner as mentioned sub (a) the dodecene carboxylicester of 19-nortestosterone is prepared in a yield of 83%. E ,,=16,200(in ethanol).

(d) In the same manner as mentioned sub (a) the tetradecene carboxylicester of 19-nortestosterone is prepared in a yield of z39,.=15,600 (inethanol).

(e) In the same manner as mentioned sub (a) the oleate of19-nortestosterone is prepared in a yield of 87%. E ,,=l5,400 (inethanol).

(7) In the same manner as mentioned sub (a) the clecanoate of19-nortestosterone is prepared in a nearly quantitative yield. The esteris an oil at room temperature. E ,,=l6,000 (in ethanol).

(g) In the same manner as mentioned sub (a) the myristate ofl9-nortestosterone is prepared in a yield of 95%. E 15,900 (in ethanol).

(h) In the same manner as mentioned sub (a) the palmitate of19-nortestosterone is prepared in a yield of 90%. [a] =+32.9 (inchloroform), E ,,=l5,300 (in ethanol), M.P. 53-56 C.

Example ll 1 g. of l9-nortestosterone and 2 g. of lauric anhydride aredissolved in 20 ml. of dry pyridine. The mixture is refluxed for 4hours. Then 2 ml. of water are added and refluxing is continued for somemore hours in order to decompose the excess of anhydride. Then themixture is evaporated to dryness, the residue is taken up in benzene,after which this benzene solution is treated in the manner of Example I.In this manner the 19-nortestosterone-17-laurate is obtained in a yield.[a] ==+37.4 (in chloroform); E ,,=l5,900; M.P. 45-46" C.

What we claim is:

1. l9-nortestosterone 17-esters of saturated straight chain aliphaticcarboxylic acids containing from 10 to 14 carbon atoms.

2. l9-nortestosterone 17-decanoate.

3. 19-nortestosterone17-laurate.

4. -19-nortestosterone 17-myristate.

References Cited in the file of this patent UNITED STATES PATENTS2,308,834 Ruzicka et a1. Jan. 19, 1943 2,756,244 Djerassi et a1. July24, 1956 2,831,873 Pinson et a1 Apr. 22, 1958 2,868,809 Donia et a1.Jan. 13, 1959 2,904,562 Diczfalusy et al. Sept. 15, 1959 2,964,537Engelfried et al. Dec. 13, 1960

1. 19-NORTESTOSTERONE 17-ESTERS OF SATURATED STRAIGHT CHAIN ALIPHATICCARNOXYLIC ACIDS CONTAINING FROM 10 TO 14 CARBON ATOMS.